Ugi-reaction-derived ionizable lipids with cyclic tertiary amine heads enable spleen-targeted mRNA delivery

  • Biomater Sci. 2025 Aug 5;13(16):4494-4501. doi: 10.1039/d5bm00738k.
Yashuai Wang  1  2 ,  Xiaoyin Liu  1 ,  Haiyin Yang  3 ,  Shuxiang Wang  1 ,  Shutao Guo  2 ,  Yuhua Weng  3 ,  Jinchao Zhang  1 ,  Luwei Li  1 ,  Kun Ge  1 ,  Xing-Jie Liang  4  5
Affiliations
  • 1. College of Chemistry & Materials Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding, 071002, China. [email protected].
  • 2. Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology and Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071 China.
  • 3. School of Life Science, Advanced Research Institute of Multidisciplinary Science, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing 100081, China.
  • 4. Chinese Academy of Sciences (CAS), Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China.
  • 5. University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
PMID: 40625181 DOI: 10.1039/d5bm00738k
Abstract

Lipid nanoparticles (LNPs) have become an important platform for nucleic acid delivery. However, LNP-mediated delivery to non-hepatic organs and specific cell types remains a non-negligible challenge. As a key component of LNPs, ionizable lipids were rationally designed to adjust the LNPs properties to achieve organ-targeted delivery. The use of the Ugi four-component reaction (Ugi-4CR) as a one-pot multicomponent synthesis strategy to construct ionizable lipid molecules offers advantages, as it enables multidimensional structural diversity of ionizable lipids. We use isocyanides with cyclic tertiary amine substituents to construct ionizable lipids via an Ugi one-pot reaction. Twenty-five ionizable lipid molecules (W1-W25) containing different cyclic tertiary amine hydrophilic heads, linkers, and hydrophobic tails were synthesized. The W19 LNPs exhibited highly selective mRNA delivery to the spleen upon intravenous administration.

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